In antitumor immune responses, CD8 cytotoxic T lymphocytes (CTL) have been identified as the most powerful effector cells (Vesely M D et al., 2011). As a consequence, most previous anti-cancer vaccines use class I HLA-restricted peptides derived from tumor antigens in order to stimulate CTL responses. However, the clinical impact of peptide-based cancer vaccines remains still modest, even if a recent gp100-derived peptide vaccination was shown to increase patient survival in melanoma (Rosenberg S A et al., 2004 and Schwartzentruber D J et al., 2011). In addition to a variety of immune suppressive mechanisms originating from the tumor itself, suboptimal design of vaccines used so far may explain this failure. In particular, short epitopic peptides, could induce vanishing CTL responses or tolerance towards targeted antigens (Bijker M S et al., 2007 and Toes R E et al., 1996). In the meanwhile, CD4 helper T cells have gained interest in anti-tumor immunity and immunotherapy. Indeed, tumor-reactive CD4+T helper 1 T cells (Th1) produce several cytokines (such as IFN-γ, TNF-α and IL-2) essential for the induction of cell-mediated immunity against tumors. One widely accepted model demonstrates the ability of CD4+ T cells to ‘license’ dendritic cells (DCs) for efficient CD8+ T cell priming through the interaction of costimulatory receptors (Bennett S R et al., 1998 and Smith C M et al., 2004). The cytokines secreted by CD4+Th1 cells also exert direct antitumor and antiangiogenic effects. Furthermore, it has been demonstrated in a mouse model that only tumor-reactive CD4+ T cells have been found to ensure efficient effector CTLs recruitment at the tumor site. In a clinical standpoint, a high density of tumor-infiltrating CD4+ Th1 cells has been recently shown as a good prognostic marker in colorectal cancer patients emphasizing the role of these cells in cancer immunosurveillance. In melanoma, tumor-reactive CD4 T cells have also been associated with a good clinical outcome (Robbins P F et al., 2002), and more recently the same group showed that tumor specific CD4 T cells were present in at least 20% of metastatic melanomas, and suggested that the infusion of TIL populations containing CD4 specific T cells could enhance the efficacy of adoptive cell therapy (Friedman K M et al., 2012). In the same line of thought, it has been demonstrated in a melanoma patient that the adoptive cell transfer of CD4 T cells specific for NYESO-1 antigen induces durable clinical remission and led to endogenous responses against non-targeted tumor antigens, suggesting the stimulation of immune responses by transferred CD4 T cells (Hunder N N et al., 2008).
In the field of peptide vaccination, it has been documented twenty years ago, in a mouse model that the generation of a strong CD8 response against a LCMV-derived peptide depended on the presence of CD4 helper T cells (Fayolle C et al., 1991). These results have been more recently confirmed in a clinical setting by the use of synthetic long peptides (SLP) in colorectal cancer, using P53 derived SLP (Speetjens F M et al., 2009), in vulvar intraepithelial neoplasia (Kenter G G et al., 2009) and cervical cancer patients (Welters M J et al., 2008) using HPV16-derived SLP. In the case of vulvar neoplasia, clinical responses appeared to be correlated with the induction of strong HPV16 specific immune responses. Synthetic long peptides containing immunogenic CD8 and CD4 tumor epitopes are therefore attractive tools to implement therapeutic cancer vaccine.
One of the main issues in the field of long peptide vaccination in solid tumors is to identify immunogenic long peptides derived from relevant tumor associated antigens. Target antigens should be widely expressed, and able to induce robust CD8 and CD4 anti-tumor T cell responses. In melanoma, the Melan-A antigen fulfills these requirements and the inventors recently reported the efficiency of a Melan-A modified SLP, to cross-prime human tumor-reactive T cells (Chauvin J M et al., 2012). Another attractive target for melanoma vaccination would be the MELOE-1 antigen (46 amino acids), specifically overexpressed in melanoma. Indeed, the inventors previously reported that the infusion of tumor infiltrating lymphocytes (TIL) specific for the MELOE-1 antigen was associated with a prolonged relapse-free survival for HLA-A2 melanoma patients who received TIL therapy (Godet Y et al., 2008). Furthermore, they documented the presence of a large and tumor reactive CD8 T cell repertoire in HLA-A2 melanoma patients (Godet Y et al., 2010) and the presence of two class II epitopes in the vicinity of the class I epitope, located at the C-terminal end of the polypeptide (Rogel A et al., 2011).
Despites these results, the identification of additional melanoma antigens with a documented immunogenic potential remains a major issue to address for melanoma immunotherapy.